Since they were first developed in the 1950s, advances in inhaler drug delivery technology have been substantial. But compared with tablets, the technology it still in its infancy. Inhaled drugs are delivered directly to the target tissue where they can act immediately, in contrast to systemic delivery methods. This localized delivery is a widely recognized benefit of inhalables, as a lower dose is generally needed to achieve therapeutic effect. Since their initial design, inhaler devices and formulations have undergone rapid innovations, most notably the introduction of hydrofluoroalkane as a propellant in metered dose inhalers, which improved the degree of drug deposition in the lung. Despite this, more improvements in inhaled delivery methods are required to further increase the drug dose reaching the lung by manipulating particle properties and therefore improving the treatment of prevalent respiratory diseases, such as chronic obstructive pulmonary disease.
The defining focus of research in the inhalable drug area has, until now, been aimed at learning how to disperse formulations efficiently enough to deliver a clinically efficacious dose – and, in particular, how to create and disperse particles of a size that facilitates deposition in the lung. The importance of this work should not be overlooked, but there are important challenges yet to be tackled. To reach new levels of performance, and to better meet patient requirements, I would argue that we now need to start asking new questions. There are three key questions that the field must address:
i) How can we develop a better understanding of aerosolization performance by extending current research?
ii) How can we better understand particle behavior on the way to the lung (especially the influence of humidity on particle properties)?
iii) How can we improve drug uptake within the lung?
The aerodynamic particle size distribution (APSD) of the therapeutic aerosol produced by an inhaler plays a key role in the physical mechanics of particle deposition in the airways – which means it directly affects the efficacy of the treatment. Understanding the dynamics of dose dispersion is therefore a critical first step towards better drug delivery control. For pressurized metered dose inhalers (pMDIs), we require a detailed understanding of the atomization and evaporation processes that determine the size of particles delivered – a major challenge, but it potentially opens up a route to higher performance efficiency. The use of innovative imaging technology to investigate the aerosol plume, in combination with the intelligent application of computational fluid dynamics, is helping to pave the way towards increasing our understanding. New knowledge will be particularly valuable as the focus of research activity shifts to the potential of extra-fine particles (those less than two microns in size), which increasingly appear to offer both clinical and product performance benefits.
Next, it is important to establish a better understanding of the patient response to inhaled particles (and vice versa), ultimately allowing researchers and clinicians to understand why patients may respond differently to the same product, according to their age or disease state. For example, during drug development and manufacture, the aerodynamic particle size distribution of inhaled drug particles is usually measured in a low humidity environment, using the technique of cascade impaction. But there’s a problem: the route the drug particles follow is close to a saturated water environment, meaning that test data may not accurately represent what is going to happen in vivo. Fine particles tend to be hygroscopic, which means that when they are subject to high humidity they will absorb water relatively rapidly because of the high surface-area-to-volume ratio, becoming larger than they were when they entered the body. In the past, inhaler testing may not have taken this into consideration. But now, researchers are paying more attention to the effects this can have on the deposition behavior of the drug, and the resulting dose received by the patient.
Oxygen levels in the lung are also known to affect the uptake and behavior of inhaled particles, as shown by research into the impact of pollutants (1). Within the lung, the steady state concentration of oxygen is significantly lower than the 21 percent used for many experiments. Once particles have deposited (frequently in an unpredictable manner), it is the respiratory tract lining fluid (RTLF) that has a defining influence on the uptake of inhaled molecules, and particle transportation at the air-lung interface. RTLF changes with age and with disease state, and therefore plays a role in the variable lung response in different patients.
Additionally, the composition of the RTLF changes depending on the region of the lung, so when particles transverse the lining, the dissolution, cellular uptake and therapeutic efficacy all depend partly upon where the drug particles reach. And that’s one reason why dissolution testing has become an important theme. Once an inhaled drug has deposited, the absorption –and, therefore, the therapeutic effectiveness of the drug – depends on the active drug dissolving in the fluid available at the target site. As it stands, there are no dissolution test methods specified for inhaled products; however, FDA grants have been released to investigate this aspect of performance.
Improved understanding of in vivo particle behavior will allow us to more closely tailor inhaled products to meet the needs of specific patient groups in a more efficient way. There is potential to be explored by developing more efficient technologies that use formulations with reduced active pharmaceutical ingredient loading. Respiratory diseases represent a huge burden on healthcare services across the globe, with developing countries in particular struggling with the associated financial weight of such conditions. By improving inhaled drug delivery uptake within the body, we have the opportunity to improve the patient experience, and at the same time reduce healthcare costs.
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